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Advancing iPSC-derived Thymic Epithelial Cells as Cell Therapy for T Cell Immune Reconstitution in Vulnerable Populations(original application ID AI190181-01)

Award Number: R01AI190181
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/08/2026
PERIOD OF PERFORMANCE END DATE: 03/31/2031

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Advancing iPSC-derived Thymic Epithelial Cells as Cell Therapy for T Cell Immune Reconstitution in Vulnerable Populations(original application ID AI190181-01) - ABSTRACT | NARRATIVE The thymus instructs T cell immunity and central tolerance, yet its therapeutic potential remains clinically untapped as the signals that drive thymic epithelial cell (TEC) differentiation remain incompletely understood. The thymic epithelium comprises a highly specialized set of cells that attract lymphoid progenitors, promote their proliferation and maturation into thymocytes, and facilitate the selection of a diverse, self-tolerant T cell receptor (TCR) repertoire. The role of the thymus in building immune identity begins before birth. The organ peaks in size in infancy and then structurally and functionally involutes over time. This process causes the decline in immune competence with age (immune senescence). The impact of this phenomenon was exposed during the COVID-19 pandemic when waning immunity left the elderly more vulnerable to adverse outcomes. Thymus insult also occurs in many patients through medications, radiation, infections and graft-versus-host disease. The most severe form of thymic compromise is congenital athymia, the inborn absence of the thymus due to genetic mutations. Genetic or acquired thymic injury leads to immunodeficiency, autoimmunity, inflammation and increased cancer risk. Regenerating thymic function, e.g., through human induced pluripotent stem cell (iPSC)-derived regenerative thymic tissues holds greatest therapeutic promise for these patients. We have used single-cell transcriptomics of human fetal anterior foregut-derived organs to uncover the signals that drive TEC differentiation. We have translated these insights into a novel differentiation platform for the derivation of TECs from iPSCs in vitro. When iPSC-derived TEC organoids are transplanted into athymic NSG nude (NSG-Foxn1-/-) mice engrafted with human hematopoietic stem cells, they function like the human thymus, giving rise to human ab-T cells with a diverse TCR repertoire, gd-T cells and regulatory T cells. In this application, we now seek to advance the translation of iPSC-derived TECs (iTECs) by testing their safety and efficacy as cell therapy for vulnerable patient populations in need of improved T cell immunity. In Aim 1, we will determine the capacity of iTECs to promote T cell reconstitution, functional antigen-specific T cell responses and the development of a broad TCR repertoire in vivo. In Aim 2, we will assess if T cells educated on iTEC are tolerant to “self” but respond to “non-self”. In addition, we will directly analyze the HLA-associated peptide repertoire presented on iTECs using immunopeptidomics. In Exploratory Aim 3, we will test if HLA-editing of iPSCs for iTECs derivation affects antigen-specific immune responses, TCR repertoire, and immunopeptidome in vivo. Advancing the translation of iPSC-derived TECs into a cell therapy is an entirely new strategy to leverage the therapeutic potential of T cells from inside the body and could begin a new chapter of immunotherapeutics.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $809,250 )
2026	2026	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Allergy and Infectious Diseases Research	000	1	4/8/2026	NEW	$809,250
														Subtotal = $809,250

Grand Total All Awards = $809,250

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Advancing iPSC-derived Thymic Epithelial Cells as Cell Therapy for T Cell Immune Reconstitution in Vulnerable Populations(original application ID AI190181-01)

Award Number: R01AI190181

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 04/08/2026

PERIOD OF PERFORMANCE END DATE: 03/31/2031

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